Francisella tularensis can cause serious illness and death in humans. F. tularensis is considered to be one of the most likely bioweapons due to ease of dissemination through aerosolization, and the high morbidity and mortality associated with inhalation tularemia. There is currently no tularemia vaccine licensed for general use, and thus human populations are at significant risk from the illicit use of F. tularensis. Very little is known about F. tularensis pathogenesis and host response, and thus fundamental research into F. tularensis biology is critical for the future development of therapeutics and vaccines against tularemia. We have assembled a group of integrated research projects focused on Francisella pathogenesis and immunity from researchers at the University of Texas San Antonio and the University of Texas Health Science Center in San Antonio. The individual projects are designed to be highly integrated with the other projects, and ultimately lead to a synergy that will propel our knowledge of this potential bioweapon such that new antimicrobial strategies can be developed. Virtually nothing is known about aerosol infections of F. tularensis subsp. tularensis (Type A), the most likely bioweapon form of tularemia, and thus this program project focuses almost exclusively on this form of tularemia. Our integrated bacteriological and immunological research approach involves four research projects and three support cores. These projects are designed to 1. identify essential and virulence factors of F. tularensis, 2. detail the immunology of inhalation tularemia in situ, 3. characterize the role of Toll-like receptors in host response, and 4. identify T cell epitopes and characterize T cell mediated responses to F. tularensis. These projects will be supported by an administrative core, a genomics core, and an immunomicroscopy core. The collaborative interactions of the investigators will ultimately lead to a dramatic increase in our understanding of pathogen-host interactions during F. tularensis subsp. tularensis aerosol infections, and facilitate the development of novel therapeutics and vaccines to combat weaponized tularemia.